The RORs have been characterized as constitutively active receptors displaying the ability to activate transcription in the absence of a ligand. The retinoic acid receptor-related orphan receptor α (RORα) is an orphan receptor that has been demonstrated to play an important role in regulation of metabolism [3]. SR3335 is a selective RORα inverse agonist that directly binds to RORα with a Ki of 220 nM [3]. In a cell-based chimeric receptor Gal4 DNA-binding domain-NR ligand binding domain cotransfection assay, SR3335 significantly inhibits the constitutive transactivation activity of RORα (IC50=480 nM)(partial inverse agonist activity), but has no effect on the activity of LXRα and RORγ [3]. Pharmacokinetic studies indicate that SR3335 displays reasonable exposure following an i.p. injection into mice. The ability of SR3335 is assessed to suppress gluconeogenesis using a diet induced obesity (DIO) mouse model where the mice where treated with 15 mg/kg b.i.d., i.p. for 6-days followed by a pyruvate tolerance test. SR3335 treated mice displays lower plasma glucose levels following the pyruvate challenge consistent with suppression of gluconeogenesis. Importantly, mice treated with SR3335 displayed no difference in body weight or food intake after 7-days of treatment with SR3335 [3].
作用机制
SR3335 is a selective RORα synthetic ligand, directly binds to RORα, but not other RORs, and functions as a selective partial inverse agonist of RORα in cell-based assays.
SR3335 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human nucleus pulposus cells
1 µM
24 hours
SR3335 treatment reversed the trend of increased apoptosis in NP cells induced by TNF-α treatment and upregulated the expression of type II collagen and aggrecan while downregulating MMP13 and ADAMTS4.
Mediators Inflamm. 2021 Jul 28;2021:9954909
HepG2 cells
5 µM
24 hours
To evaluate the inhibitory effect of SR3335 on endogenous RORα target gene expression, results showed that SR3335 significantly suppressed G6Pase and PEPCK mRNA expression.
ACS Chem Biol. 2011 Mar 18;6(3):218-22
HEK293 cells
5 µM
24 hours
To evaluate the inhibitory effect of SR3335 on RORα transcriptional activity, results showed that SR3335 significantly suppressed transcription driven by the G6Pase promoter.
ACS Chem Biol. 2011 Mar 18;6(3):218-22
Chick bursal B lymphocytes
5 µM
30 min pretreatment
Inhibited B-lymphocyte apoptosis, decreased IL-6, TNF-α, IFN-γ and ROS production, down-regulated RORα/RORγ mRNA level and p-iκB, p-p65 protein expression, whereas improved IL-10 level and Nrf2, HO-1 protein expression.
Antioxidants (Basel). 2022 Apr 8;11(4):748.
Chick thymic lymphocytes
5 µM
30 min pretreatment followed by 44 hours culture
SR3335 enhanced the stimulative effect of melatonin on p-AKT expression and increased the expression levels of β-catenin and CyclinD1
Poult Sci. 2024 Dec;103(12):104507
B lymphocytes
5 µM
30 minutes
To investigate the effect of SR3335 on GL-induced B lymphocyte proliferation. Results showed that pretreatment with SR3335 increased B lymphocyte proliferation by 7.88%.
Poult Sci. 2020 Sep;99(9):4294-4302
T lymphocytes
5 µM
30 minutes
To investigate the effect of SR3335 on GL-induced T lymphocyte proliferation. Results showed that pretreatment with SR3335 increased T lymphocyte proliferation by 12.48%.
Poult Sci. 2020 Sep;99(9):4294-4302
Human chondrocytes
0.5-1 µM
48 hours
SR3335 treatment upregulated the expression of COL2A1 and SOX9 while suppressing ADAMTS4 and MMP13, indicating it promotes extracellular matrix synthesis and inhibits degradation in chondrocytes.
Cell Death Dis. 2021 Sep 28;12(10):886.
Primary neonatal cardiac fibroblasts
20 µM
48 hours
SR3335 promoted cell injury and proliferation, enhanced collagen synthesis, facilitated oxidative stress and necroptosis in cardiac fibroblasts with high glucose stimulation
Front Pharmacol. 2025 Jan 30;16:1539690
Chicken thymic lymphocytes
5 µM
48 hours
SR3335 (ROR α antagonist) attenuated the melatonin-induced increase in Bcl-2 protein levels and decrease in Bax protein levels.
Poult Sci. 2024 Feb;103(2):103331
Human CD4+ T cells
5 µM
6 days
To evaluate the effect of SR3335 on IL-17A expression in human CD4+ T cells under TH17-polarizing conditions. Results showed that SR3335 dose-dependently inhibited IL-17A expression.
Nat Commun. 2021 Jan 4;12(1):76
Mouse CD4+ T cells
5 µM
96 hours
To evaluate the effect of SR3335 on IL-17A expression in mouse CD4+ T cells under TH17-polarizing conditions. Results showed that SR3335 dose-dependently suppressed IL-17A expression without affecting cell viability.
Nat Commun. 2021 Jan 4;12(1):76
SR3335 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
RORα-knockout (sg/sg) mice
Intraperitoneal injection
10 mg/kg
4 consecutive days
SR3335 reduced TG content in the liver and plasma, and increased plasma glycerol concentration, suggesting an activation of adipose lipolysis.
Sci Rep. 2025 Mar 26;15(1):10464
Sprague-Dawley rats
Needle puncture-induced intervertebral disc degeneration model
Intraperitoneal injection
10 mg/kg/day
Every 3 days for 4 weeks
SR3335 treatment restored the expression of aggrecan and reduced the expression of the apoptosis marker cleaved caspase 3.
Mediators Inflamm. 2021 Jul 28;2021:9954909
Mice
LPS-induced endotoxic shock model
Intraperitoneal injection
15 mg/kg
Once daily for 7 days
To evaluate the protective effect of SR3335 on LPS-induced endotoxic shock, results showed that SR3335 significantly improved survival and clinical scores in mice
Front Immunol. 2021 Mar 9;12:647329
C57BL/6 mice
Diet-induced obesity model
Intraperitoneal injection
15 mg/kg
Twice daily for 6 days
To evaluate the inhibitory effect of SR3335 on gluconeogenesis, results showed that SR3335 significantly reduced plasma glucose levels, indicating its suppression of gluconeogenesis.
ACS Chem Biol. 2011 Mar 18;6(3):218-22
Mice
Experimental autoimmune encephalomyelitis (EAE) model
Intraperitoneal injection
30 mg/kg
Twice daily, for the duration of the experiment
To evaluate the therapeutic effect of SR3335 in the EAE model. Results showed that SR3335 significantly reduced the relapse rate and severity of relapse, and inhibited inflammatory cell infiltration in the CNS.
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